Diltiazem, (+) cis 3-(acetyloxy)-5-[2-(dimethylamino)ethyl]-2,3-dihydro-2-(4-methoxyphenyl)-1 ,5-benzothiazepin-4(5H)one, is a calcium antagonist that is marketed by Marion Merrell Dow under the tradename Cardizem.RTM.. The compound can be utilized in the treatment of cardiovascular disorders such as angina, arrhythmias, and hypertension. Typical doses range from 120-360 mg/day. Cardizem.RTM. is currently commercially available in two dosage forms in the United States. One of the forms is a rapid release tablet which must be administered from 3-4 times daily. The other is a sustained release tablet which is suitable for bid dosage regimens. A formulation suitable for once a day (qd) administration is not currently commercially available in the United States. Numerous studies have shown that patient compliance increases substantially with medication regimens requiring only one dose per day. Thus it would be a valuable contribution to the art to develop a diltiazem formulation suitable for qd administration.
The pharmacokinetics of a drug can have a considerable impact on whether a particular dosage form will produce satisfactory results after in-vivo administration. Orally administered drugs are absorbed and enter the capillaries and veins of the upper GI tract and are transported by the portal vein directly to the liver before entering the general circulation of the body. The entire absorbed dose of a drug is exposed to the liver during its first pass through the body. If a drug is subject to a high hepatic clearance (i.e. rapidly metabolized by the liver), then a substantial fraction of the absorbed dose is extracted from the blood and metabolized before it reaches the systemic circulation. This phenomenon is termed the first pass effect. The consequence of this phenomenon is a significant decrease in bioavailability. In some instances, the first pass effect is so large as to render oral administration of a drug ineffectual.
The pharmacokinetics of diltiazem have been studied extensively. Diltiazem is well absorbed from the gastrointestinal tract and is subjected to an extensive first pass effect giving an absolute bioavailability of 40% (when compared with intravenous administration.) At therapeutic doses, approximately 60% of the administered diltiazem is metabolized before the compound has had a chance to reach its site of action. Compounds such as diltiazem which are subject to a first pass effect are considered to have non-linear pharmacokinetics. An increase or decrease in the dose administered will not necessarily produce the corresponding increase or decrease in observed blood levels. This is dependent upon whether the metabolic level of the liver has been exceeded.
Authors such as Urquhart et al have recognized that it can be difficult to design extended release formulations for compounds subjected to a first pass effect. CONTROLLED-RELEASE PHARMACEUTICALS, American Pharmaceutical Association (1979). Whereas a rapid release tablet allows saturation of the enzymes and a significant increase in blood levels, a sustained release tablet releasing similar quantities of drugs at a zero order rate will typically not produce such saturation of metabolic capacity. A larger percentage of the sustained release dose will be metabolized before it has had an opportunity to reach its site of action resulting in sub-therapeutic levels over a significant portion of the dosing period.
Controlled release formulations are designed to release significant quantities of drug only at specific timed intervals. If the release occurs at appropriate times, therapeutic levels will be maintained over an extended dosing period such as 12 or 24 hours. An inappropriate release pattern may subject the patient to toxic levels over part of the dosing period and sub-therapeutic levels over other portions of the dosing period. The particular time at which drug should be released varies significantly with each drug and is dependent upon its unique pharmacokinetics. The difficulty of correctly predicting an appropriate release pattern is well known to those skilled in the art.
U.S. Pat. No. 4,894,240 discloses a controlled release diltiazem formulation. The '240 patent states that its formulation is suitable for once a day administration. The formulation is prepared from diltiazem beads in which a diltiazem core is enveloped by a multilayer film in which the film is composed of a major component of a water insoluble polymer and a minor component of a water soluble polymer. Suitable water insoluble polymers include various cellulose esters, polyoxides, polyacrylates, polyethylene, polypropylene, polyurethane, polyvinyl, etc. A proprietary polymer composed of aryrlic resins sold under the tradename, EUDRAGIT, is also specified as being suitable. Suitable water soluble polymers include polyvinylalcohol, polyvinylpyrrolidone, methyl cellulose, and polyethylene glycol. A proprietary acrylate polymer sold under the trademark EUDRAGIT RL is also specified as being suitable. The '240 patent specifies that from 60-95% of the diltiazem should be released from the controlled release dosage form within 13 hours of administration. This release pattern produces peak plasma levels approximately 12-14 hours after administration. Minimal diltiazem is released from the formulation after 13 hours. Although the '240 patent is a valuable contribution to the art, it has been discovered that formulations manufactured with these beads do not maintain optimum blood levels of diltiazem over the entire 24 hour dosing period. Blood levels of diltiazem fall significantly before the next dose is administered resulting in a significant variance between peak and trough levels. Thus it would be a valuable contribution to the art to develop a diltiazem formulation that would optimize diltiazem levels throughout a 24 hour dosing period by minimizing the variance between peak and trough levels.